Ribosomal S6 kinase (RSK) plays a critical role in DNA damage response via the phosphorylation of histone lysine demethylase KDM4B.

Background: Epigenetic dysregulation affecting oncogenic transcription and DNA damage response is a hallmark of cancer. The histone demethylase KDM4B, a factor regulating these processes, plays important roles in estrogen receptor-mediated transcription and DNA repair in breast cancer. However, how oncogenic phospho-signal transduction affects epigenetic regulation is not fully understood.

The cytokine profile correlates with less tumor-infiltrating lymphocytes in luminal A breast cancer.

Purpose: Tumor-infiltrating lymphocyte (TIL) levels are prognostic and predictive factors for breast cancer. Unlike other subtypes, most luminal A breast cancers are immune deserts; however, the underlying mechanisms are poorly understood.

Methods: Immune-related cytokines, chemokines, and growth factors were measured in the sera of 103 patients with breast cancer using a multiplex panel.

Neutrophil-to-lymphocyte ratio at the end of treatment with CDK4/6 inhibitors is an independent prognostic factor for ER-positive HER2-negative advanced breast cancer.

Purpose: The aim of this study was to elucidate the clinical significance of peripheral blood biomarkers, including absolute lymphocyte count (ALC) and neutrophil-to-lymphocyte ratio (NLR), at the end of treatment (EOT) with CDK4/6 inhibitors abemaciclib and palbociclib in patients with estrogen receptor-positive human epidermal growth factor receptor 2-negative advanced breast cancer.

Methods: We included 67 patients treated with fulvestrant plus abemaciclib or palbociclib. Overall survival (OS) since the EOT with CDK/4/6 inhibitors was compared in relation to the levels of ALC and NLR.

Prognostic value of the 21-Gene Breast Recurrence Score® assay for hormone receptor-positive/human epidermal growth factor 2-negative advanced breast cancer: subanalysis from Japan Breast Cancer Research Group-M07 (FUTURE trial).

Purpose: This study aimed to determine whether the 21-Gene Breast Recurrence Score® assay from primary breast tissue predicts the prognosis of patients with hormone receptor-positive and human epidermal growth factor 2-negative advanced breast cancers (ABCs) treated with fulvestrant monotherapy (Group A) and the addition of palbociclib combined with fulvestrant (Group B), which included those who had progression in Group A from the Japan Breast Cancer Research Group-M07 (FUTURE trial).

Methods: Progression-free survival (PFS) and overall survival (OS) were compared using the log-rank test and Cox regression analysis based on original recurrence score (RS) categories (Low: 0-17, Intermediate: 18-30, High: 31-100) by treatment groups (A and B) and types of ABCs (recurrence and de novo stage IV).

Results: In total, 102 patients [Low: n = 44 (43.

Trastuzumab deruxtecan versus treatment of physician's choice in patients with HER2-positive metastatic breast cancer (DESTINY-Breast02): patient-reported outcomes from a randomised, open-label, multicentre, phase 3 trial.

Background: In DESTINY-Breast02, patients with HER2-positive unresectable or metastatic breast cancer who received trastuzumab deruxtecan demonstrated superior progression-free and overall survival compared with those receiving treatment of physician's choice. We present the patient-reported outcomes (PROs) and hospitalisation data.

Methods: In this randomised, open-label, phase 3 trial conducted at 227 clinical sites globally, enrolled patients had to be aged 18 years or older with HER2-positive unresectable or metastatic breast cancer that had progressed on trastuzumab emtansine and had an Eastern Cooperative Oncology Group performance status of 0 or 1.

Targeting Sphingosine-1-Phosphate Signaling in Breast Cancer.

In recent years, newly emerging therapies, such as immune checkpoint inhibitors and antibody-drug conjugates, have further improved outcomes for breast cancer patients. However, recurrent and metastatic breast cancer often eventually develops resistance to these drugs, and cure is still rare. As such, the development of new therapies for refractory breast cancer that differ from conventional mechanisms of action is necessary.

Correlation between postoperative treatment selection and prognosis determined using the Oncotype DX® test data: a retrospective multicenter study in Japan.

Purpose: Oncotype DX® is a frequently used multigene assay for hormone receptor-positive breast cancers. However, limited evidence is available regarding its application in Japan owing to the lack of insurance coverage. Therefore, we conducted this large-scale, retrospective study by collecting data from nine Japanese institutes and assessed postoperative treatment choice and prognosis by using Oncotype DX®.

Association of Neutrophil-to-Lymphocyte Ratio and Absolute Lymphocyte Count With Clinical Outcomes in Advanced Breast Cancer in the MONARCH 2 Trial.

Background: Established prognostic factors for treatment response to cyclin-dependent kinases 4 and 6 inhibitors are currently lacking. We aimed to investigate the relationship of pretreatment neutrophil-to-lymphocyte ratio (NLR) and absolute lymphocyte count (ALC) to abemaciclib outcomes.

Patients And Methods: This was a post hoc analysis of data from MONARCH 2, a phase III study of abemaciclib or placebo plus fulvestrant in hormone-receptor positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer that progressed on endocrine therapy.

Baseline interleukin-6 is a prognostic factor for patients with metastatic breast cancer treated with eribulin.

Purpose: Eribulin is a unique anti-cancer drug which can improve overall survival (OS) of patients with metastatic breast cancer (MBC), probably by modulating the tumor immune microenvironment. The aim of this study was to investigate the clinical significance of serum levels of immune-related and inflammatory cytokines in patients treated with eribulin. Furthermore, we investigated the association between cytokines and immune cells, such as myeloid-derived suppressor cells (MDSCs) and cytotoxic and regulatory T cells, to explore how these cytokines might affect the immune microenvironment.

Intratumoral Tumor Infiltrating Lymphocytes (TILs) are Associated With Cell Proliferation and Better Survival But Not Always With Chemotherapy Response in Breast Cancer.

Objective: To investigate the clinical relevance of intratumoral tumor infiltrating lymphocytes (TILs) in breast cancer as measured by computational deconvolution of bulk tumor transcriptomes.

Summary Background Data: Commonly assessed TILs, located in tumor stroma without direct contact with cancer cells (stromal TILs), correlate with breast cancer treatment response and survival. The clinical relevance of intratumoral TILs has been less studied partly due to their rarity; however, they may have nonnegligible effects given their direct contact with cancer cells.

An increase in tumor-infiltrating lymphocytes after treatment is significantly associated with a poor response to neoadjuvant endocrine therapy for estrogen receptor-positive/HER2-negative breast cancers.

Background: The reason for the poor prognosis of estrogen receptor (ER) + /human epidermal growth factor receptor 2 (HER2)- breast cancer patients with high levels of tumor-infiltrating lymphocytes (TILs) is poorly understood. The association between TILs and response to neoadjuvant endocrine therapy (NET) was examined.

Methods: We recruited 170 patients with ER + /HER2- breast cancer who were treated with preoperative endocrine monotherapy.

Copy number alteration is an independent prognostic biomarker in triple-negative breast cancer patients.

Background: Next-generation sequencing (NGS) has enabled comprehensive genomic profiling to identify gene alterations that play important roles in cancer biology. However, the clinical significance of these genomic alterations in triple-negative breast cancer (TNBC) patients has not yet been fully elucidated. The aim of this study was to clarify the clinical significance of genomic profiling data, including copy number alterations (CNA) and tumor mutation burden (TMB), in TNBC patients.

Relationship between FDG-PET and the immune microenvironment in breast cancer.

Objective: To investigate the relationship between fluorodeoxyglucose (FDG) uptake (maximum standardised uptake value [SUVmax]) and immune markers (tumour-infiltrating lymphocytes [TILs] and neutrophil-to-lymphocyte ratio [NLR]) and evaluate the potential prognostic value of any correlations.

Methods: Data from 502 patients with breast cancer, including 346 oestrogen receptor (ER)-positive / human epidermal growth factor receptor 2 (HER2)-negative, 88 HER2-positive, and 68 triple-negative cases, who had undergone surgery were reviewed. Relationships between the clinicopathological factors, SUVmax, TILs, NLR, recurrence-free survival (RFS), and overall survival of all patients and each subtype were evaluated using a Cox proportional hazards model and log-rank test.

Lack of impact of the ALDH2 rs671 variant on breast cancer development in Japanese BRCA1/2-mutation carriers.

The aldehyde degrading function of the ALDH2 enzyme is impaired by Glu504Lys polymorphisms (rs671, termed A allele), which causes alcohol flushing in east Asians, and elevates the risk of esophageal cancer among habitual drinkers. Recent studies suggested that the ALDH2 variant may lead to higher levels of DNA damage caused by endogenously generated aldehydes. This can be a threat to genome stability and/or cell viability in a synthetic manner in DNA repair-defective settings such as Fanconi anemia (FA).

Absolute Lymphocyte Count Is an Independent Prognostic Factor for ER-positive HER2-negative Advanced Breast Cancer Patients Treated With CDK4/6 Inhibitors.

Background/aim: The aim of this study was to elucidate the clinical significance of peripheral blood biomarkers, including absolute lymphocyte count (ALC), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and C-reactive protein (CRP) in patients with estrogen receptor-positive human epidermal growth factor receptor 2-negative advanced breast cancer treated with the CDK4/6 inhibitors, abemaciclib and palbociclib.

Patients And Methods: A total of 83 patients treated with fulvestrant plus abemaciclib or palbociclib were included in this study. Progression-free survival (PFS) and overall survival (OS) were compared in relation to baseline levels of ALC, NLR, PLR and CRP.

Total Lesion Glycolysis Levels as Predictive Indicators in Patients With Metastatic and Recurrent Breast Cancer Undergoing Endocrine Therapy With or Without CDK4/6 Inhibitor.

Background/aim: Endocrine therapy (ET) with or without CDK4/6 inhibitors is the primary treatment choice for patients with estrogen receptor (ER)-positive and HER2-negative subtype of metastatic breast cancer (MBC). We examined the metabolic parameters identified using F-fluorodeoxyglucose-positron emission tomography (FDG-PET) in terms of sensitivity, since no predictive factors exist.

Patients And Methods: We included 136 patients with MBC treated with ET alone (n=107) or combined with CDK4/6 inhibitor (n=29) and examined using FDG-PET before treatment began.

Early assessment of tumor response using F-FDG PET/CT after one cycle of systemic therapy in patients with recurrent and metastatic breast cancer.

Objective: This study was conducted to evaluate the usefulness of early assessment of tumor response using fluorine-18-fludeoxyglucose positron emission tomography/computed tomography (F-FDG PET/CT) after one cycle of systemic therapy in patients with recurrent and metastatic breast cancer.

Subject And Methods: Thirty-three patients with recurrent or metastatic breast cancer underwent F-FDG PET/CT before and after one cycle of systemic therapy. Based on the European Organization for Research and Treatment of Cancer (EORTC) criteria, the maximum standardized uptake value (SUVmax) of the same lesions (up to a total of five) noted in the baseline and follow-up scans were summed (maximum of two per organ) as target lesions, and therapeutic response was evaluated.

Alteration of Trop-2 expression in breast cancer cells by clinically used therapeutic agents and acquired tamoxifen resistance.

Background: Sacituzumab govitecan is an antibody-drug conjugate that delivers SN-38, an active metabolite of irinotecan, to the target molecule, trophoblast cell-surface antigen 2 (Trop-2). It is a promising drug for triple-negative breast cancer and is anticipated to be effective for luminal breast cancer. The efficacy of the agent relies on the expression of Trop-2 rather than its intracellular function.

Low intratumoral genetic neutrophil-to-lymphocyte ratio (NLR) is associated with favorable tumor immune microenvironment and with survival in triple negative breast cancer (TNBC).

Patients with triple negative breast cancer (TNBC) have a poor prognosis. A novel prognostic biomarker may guide management by appropriately selecting patients for particular treatments. Peripheral blood neutrophil-to-lymphocyte ratio (NLR) was reported to associate with cancer progression, thus we hypothesized that intratumor genetic NLR will reflect tumor immune microenvironment (TIME) and breast cancer biology.

Investigation of a Novel S-1 Administration Schedule for Treating Metastatic and Recurrent Breast Cancer (KBCOG13).

Background/aim: S-1, a 5-fluorouracil(5-FU) oral anti-cancer drug, has been traditionally used with a schedule of 4-week oral administration followed by 2-week rest for breast cancer treatment. We, herein, aimed to investigate the clinical efficacy and safety of a schedule of 2-week oral administration followed by 1-week rest for patients with metastatic breast cancer.

Patients And Methods: We enrolled patients with HER2-negative metastatic breast cancer who had not received prior chemotherapy.

Japanese subpopulation analysis of MONARCH 2: phase 3 study of abemaciclib plus fulvestrant for treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer that progressed on endocrine therapy.

Background: This was a Japanese subpopulation analysis of MONARCH 2, a double-blind, randomized, placebo-controlled, phase 3 study of abemaciclib plus fulvestrant in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer (ABC).

Methods: Eligible women had progressed on (neo)adjuvant endocrine therapy (ET), ≤ 12 months from end of adjuvant ET, or on first-line ET for ABC, and had not received chemotherapy for ABC. Patients were randomized 2:1 to receive abemaciclib or placebo plus fulvestrant.

Indices of peripheral leukocytes predict longer overall survival in breast cancer patients on eribulin in Japan.

Background: It was reported that eribulin regulates the tumor microenvironment, including the immune system, by inducing vascular remodeling. Lymphocyte counts are a critical index of immune response in patients. The non-Asian, global EMBRACE study has suggested that baseline absolute lymphocyte count (ALC) may be a predictor of the survival benefit of eribulin in breast cancer patients.